The aim of this proposal is to understand the structure and the molecular genetic origins of anti-DNA antibodies found in patients with SLE. I will study antibodies reactive with the monoclonal anti-idiotype F4 that recognizes a heavy chain determinant on cationic IgG anti-DNA antibodies from patients with SLE. I will examine the antigenic fine specificity of F4 reactive antibodies from SLE sera and EBV transformed B cell lines and correlate antigenic specificity with primary amino acid sequence of heavy and light chains. By cloning the VH genes of F4 reactive antibodies from human cell lines, I will determine how many gene families are used by SLE patients to encode F4 reactive antibodies. I hope to determine at the molecular level whether F4 reactive autoantibodies are encoded by genes found only in autoimmune individuals and whether they are encoded by germline genes or represent somatic events. I hope these studies will lead to an understanding of how autoantibodies arise and help suggest how normal regulation of these antibodies is achieved.